Opioid agonists exert an agonist effect at specific, saturable opioid receptors in the CNS and other tissues. In man, opioid agonists may produce any of a variety of effects including analgesia.
Thebaine, a compound derived from opium, although having no medicinal use in itself, is useful as a starting material in synthetic schemes for the production of many opioid agonists, e.g., oxycodone. In other schemes, codeine can be utilized as the starting material for the production of many opioids, α, β-unsaturated ketones are a precursor to the opioid analgesic in many synthetic pathways. For example, 14-hydroxycodeinone is a precursor to oxycodone. Accordingly, an amount of α, β-unsaturated ketone is present as an impurity in opioid analgesic compositions.
Methods of producing thebaine or 14-hydroxy substituted opium derivatives have been reported, e.g. in U.S. Pat. No. 3,894,026 and U.S. Pat. No. 4,045,440.
The oxidation of codeine to codeinone, an initial step in the synthesis of opium derivatives has been reported in EP 0889045, U.S. Pat. No. 6,008,355, and in the J. Am. Chem. Soc, 1051, 73, 4001 (Findlay).
The reaction of codeinone to unsaturated ketone has been reported in U.S. Pat. No. 6,008,355, and in Tetrahedron 55, 1999 (Coop and Rice).
The methylation of codeinone to thebaine has been reported in Heterocycles, 1988, 49, 43-7 (Rice), and EP0889045.
U.S. Pat. No. 6,177,567 describes the hydrogenation of unsaturated ketone to oxycodone by reduction with diphenylsilane and Pd(Ph3P)/ZnC12 or with sodium hypophosphite in conjunction with a Pd/C catalyst in aqueous acetic acid.
Krabnig et al. in “Optimization of the Synthesis of Oxycodone and 5-Methyloxycodone” Arch. Pharm. (1996), 329(6), (325-326) describes hydrogenating a solution of unsaturated ketone in glacial acetic acid with a Pd—C-catalyst at 30 psi at the described conditions.
There is a continuing need in the art to provide improved methods for hydrogenating α, β-unsaturated ketones to produce the corresponding saturated ketone.
All references cited herein are incorporated by reference in their entireties for all purposes.